Chronic infection with HCV is a major health problem associated with increased risk for chronic liver disease, cirrhosis, hepatocellular carcinoma, and liver failure. HCV is a hepacivirus member of the Flaviviridae family of RNA viruses that affect animals and humans. The genome is a single ˜9.6-kilobase strand of RNA, and consists of one open reading frame that encodes for a polyprotein of ˜3000 amino acids flanked by untranslated regions at both 5′ and 3′ ends (5′- and 3′-UTR). The polyprotein serves as the precursor to at least 10 separate viral proteins critical for replication and assembly of progeny viral particles. The organization of structural and non-structural proteins in the HCV polyprotein is as follows: C-E1-E2-p7-NS2-NS3-NS4a-NS4b-NS5a-NS5b. Because the replicative cycle of HCV does not involve any DNA intermediate and the virus is not integrated into the host genome, HCV infection can theoretically be cured. While the pathology of HCV infection affects mainly the liver, the virus is found in other cell types in the body including peripheral blood lymphocytes.
HCV is the major causative agent for post-transfusion and for sporadic hepatitis. Infection by HCV is insidious in a high proportion of chronically infected (and infectious) carriers who may not experience clinical symptoms for many years. An estimated 170 million chronic carriers worldwide are at risk of developing liver disease. See, for example, Szabo, et al., Pathol. Oncol. Res. 2003, 9:215-221, and Hoofnagle J H, Hepatology 1997, 26:15S-20S. In the United States alone 2.7 million are chronically infected with HCV, and the number of HCV-related deaths in 2000 was estimated between 8,000 and 10,000, a number that is expected to increase significantly over the next years.
Historically, the standard treatment for chronic HCV was interferon alpha (IFN-alpha), particularly, pegylated interferon (PEG-IFN) alpha, in combination with ribavirin, which required six to twelve months of treatment. This combination regimen included 48 weekly injections of interferon and daily doses of oral ribavirin HCV patients infected with the genotype 1 virus.
IFN-alpha belongs to a family of naturally occurring small proteins with characteristic biological effects such as antiviral, immunoregulatory, and antitumoral activities. Interferons are produced and secreted by most animal nucleated cells in response to several diseases, in particular viral infections. IFN-alpha is an important regulator of growth and differentiation affecting cellular communication and immunological control. Treatment of HCV with interferon has frequently been associated with adverse side effects such as fatigue, fever, chills, headache, myalgias, arthralgias, mild alopecia, psychiatric effects and associated disorders, autoimmune phenomena and associated disorders and thyroid dysfunction.
Ribavirin, an inhibitor of inosine 5′-monophosphate dehydrogenase (IMPDH), enhances the efficacy of IFN-alpha in the treatment of HCV. Despite the introduction of ribavirin, more than 50% of the patients do not eliminate the virus with the current standard therapy of interferon-alpha (IFN) and ribavirin. Also, a number of patients still have significant side effects related to ribavirin. Ribavirin causes significant hemolysis in 10-20% of patients treated at currently recommended doses, and the drug is both teratogenic and embryotoxic.
A number of additional approaches are being pursued to combat the virus. These include, for example, application of antisense oligonucleotides or ribozymes for inhibiting HCV replication. Furthermore, low-molecular weight compounds that directly inhibit HCV proteins and interfere with viral replication are considered as attractive strategies to control HCV infection. Among the viral targets, the NS3/4A protease/helicase, the NS5B RNA-dependent RNA polymerase, and the non-structural NS5A protein, are considered the most promising HCV viral targets for new drugs. Indeed, compounds said to be useful for treating HCV infections are disclosed, for example, in WO2005/051318 (Chunduru, et al.) and WO2009/023179 (Schmitz, et al.). These references disclose methods for preparing the compounds, compositions comprising the compounds, compositions comprising the compounds and additional compounds, and methods of treating HCV.
Recently, two HCV therapeutic drugs have been approved in the US; each used as 3-way combination therapies in conjunction with pegylated interferon and ribavirin. These are Vertex's and Johnson and Johnson's NS3/4A protease inhibitor, Incivek® (telaprevir)                and Merck's NS3/4A protease inhibitor, Victrelis® (boceprevir). The older 2-way pegylated interferon and ribavirin treatment regimen for HCV only cured about 40% of genotype 1 infected patients. Adding Victrelis® to that regimen shortens treatment duration for some and improves cure rates to more than 60%. Likewise, adding Incivek® to that regimen shortens treatment and boosts cure rates to as high as 80%.        Unfortunately, neither Victrelis® nor Incivek® can be used alone without also including the pegylated interferon and ribavirin regimen, which brings along their concomitant unfavorable side effect profiles. These protease inhibitors also are associated with additional side effects such as rash and increased neutropenia. Such single active agent drugs also increase the risk of selecting for particular HCV mutations within the patient's body, which are resistant to these protease inhibitors.        
Even with these recent improvements, a substantial fraction of patients do not respond with a sustained reduction in viral load and there is a clearly a need for more effective antiviral therapy of HCV infection. Therefore, what is needed is a combination therapy strategy to combat the HCV virus without having to include the problematic pegylated interferon and ribavirin therapeutics. Multiple combination therapies that include Direct-acting antivirals (DAA) targeted to more than one particular type of HCV protein could reduce the incidence of side effects. Just as importantly, DAAs could reduce the virus's ability to mutate within the patient's body, which can lead to a resurgence of HCV viral titer.
In view of the worldwide epidemic level of HCV, the limited treatment options available, and the need to expand access to all oral DAA regimens, there is a an ever growing need for new effective drugs for treating chronic HCV infections.